Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 556

In addition to plasmalemmal receptor for the serine peptidase FVIIa, a soluble
form of tissue factor (TF S ) originates from an alternatively spliced transcript (TF AS )
that lacks a transmembrane domain [ 1024 ]. Compound TF AS can circulate in blood.
It has procoagulant activity when exposed to phospholipids.
Tissue factor initiates the blood coagulation cascade, as it operates as
high-affinity receptor for coagulation factor-VII. Activated coagulation factor-
VII (FVIIa) activates coagulation factor-IX and -X, ultimately causing thrombin
formation.

Common Pathway

The common pathway begins with activation of coagulation factor-X by coagulation
factor-IXa and/or -VIIa. The process requires coagulation factor-VIIIa. Thrombin
(Tn) is then produced. 136 Activated coagulation factor-X activates thrombin, re-
quiring coagulation factor-Va, via a positive feedback loop by thrombin itself like
coagulation factor-VIII. Thrombin not only converts fibrinogen to fibrin, but also
activates coagulation factor-VIII and -V as well as their inhibitor protein-C, in
addition to platelets. Fibrin strands appear where the platelets adhere, change in
shape, and aggregate.
Prothrombin is a 72-kDa single-chain glycoprotein. Its N-terminus is removed
after proteolytic activation by factor-Xa. Its C-terminus contains Ser peptidase
domain of thrombin. Carboxylation of its N-terminus in the presence of vitamin-
K is followed by additional binding of calcium and phospholipid and proteolysis by
FXa. Cleavage of prothrombin by coagulation factor-Xa creates prothrombin frag-
ments of N-terminus and prethrombin-2 [ 1026 ]. Prethrombin-2 cleavage produces
meizothrombin. Processing can generate

-thrombin or procoagulant prethrombin-
2 that accumulates in the plasma. The latter binds to platelet-membrane glycoprotein
GP4 and boosts platelet aggregation. Another substance, platelet-agglutinating
protein PAP37 has similar characteristics to prethrombin-2 [ 1026 ].
Coagulation is a controlled process. Cofactors and inhibitors are required for
the coagulation cascade. Calcium, phospholipids, and membrane constituents are
cofactors for activation of coagulation factor-VII, -IX, -X, and -II. Such interactions
are possible if vitamin-K is operating during coagulation factor synthesis.
Thrombin leads to a positive feedback of blood coagulation by activating
platelets and coagulation factor-XI and inhibits coagulation by stimulating protein-
C via thrombomodulin binding. Activated protein-C binds to protein-S and degrades
coagulation factor-Va and -VIIIa.
Serine peptidase inhibitors (serpins) inhibit substrate peptidases by forming a
stable complex with the enzyme. Several serpin-peptidase complexes are removed
from the circulation by a clearance receptor in the liver. This clearance receptor is

α

136 Thrombin binds to G-protein-coupled peptidase-activated receptors (PAR). Thrombin activation
of PAR 1 requires ADP to stimulate Gi.